Abstract

Autophagy and senescence are two important cellular processes that have been shown to play critical roles in the regulation of carcinogenesis. Our previous studies have demonstrated that cellular features of both autophagy and senescence were induced in response to penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG), a polyphenolic anti-cancer compound, in multiple types of cancer cells. In this follow-up study, we further investigated the cross-talk among these PGG-induced phenotypes and signal transduction mechanisms. In cell culture models, we show that inhibition of autophagy by either chemical inhibitors or genetic approaches (RNA interference) led to a near abolishment of PGG-induced senescence, followed by induction of apoptosis, indicating autophagy is required for the senescent phenotype induced by PGG and antagonistic of apoptosis execution. In addition, we identify unfolded protein responses (UPR) in the endoplasmic reticulum (ER) to play a pivotal role in autophagy-mediated senescence phenotype. Furthermore, our data show that c-Jun NH(2)-terminal kinase (JNK) could be a critical mediator for PGG-induced autophagy. In a subcutaneous xenograft mouse model of human HepG2 liver cancer, we detected biochemical markers of modulations of autophagy, ER stress and senescence induced by PGG intra-peritoneal administration for 16 days. Our findings provided novel insights into cellular processes and signaling mechanisms involved in PGG-induced senescence-like growth arrest in human cancer cells.